PAULJ. KROPP
3280 [CONTRIBUTION FROM THE PROCTER
Vol. 85
& GAMBLE CO., MIAMIF'ALLEY LABORATORIES, CINCINNATI 39,
The Dienone-Phenol Rearrangement.
OHIO]
A Novel Example of Ring B Cleavage
B Y PAULJ . KROPP RECEIVED APRIL 29. 1963 Acid-catalyzed rearrangement of 4ap,8rr-dimethyl-5,6,7,8-tetrahydro-2(4aH)-naphthalenone (lb) gave 4,8-dimethyl-5,6,7,8-tetrahydro-l-naphthol (4b) and 4,8-dimethyl-5,6,7,8-tetrahydro-2-naphthol (3b), with the former product predominating under either aqueous or anhydrous conditions. This is in contrast with the usual predominance of a m-cresol-type product (e.g., 3) under aqueous conditions for such rearrangements. The 8,8a-seco derivatives 12, 13a, and 13b were also formed under various conditions; these represent the first reported examples of ring B cleavage during an acid-catalyzed dienone-phenol rearrangement. The phenol 3b was identified by a n independent synthesis starting with P-(4-methoxy-2-methyI-l-benzoyl)-propionic acid (14), obtained by the succinoylation of m-methylanisole. Contrary to previous reports, this latter reaction gave, in addition, the 2-methoxy-4-methyl isomer 15, from which 7,8-dihydro-3,5-dimethyl-l-naphthol (19b) was prepared
Cross-conjugated cyclohexadienones of the type 1 undergo facile isomerization to phenolic products on treatment with aqueous mineral acids or with acetic anhydride containing acidic catalysts. A mixture of two phenols is generally obtained, which result from two separate pathways involving 1,2-methyl migration (path A, Chart I ) in one case and rearrangement through an intermediate spiro carbonium ion 5 (path B) in the other. 1-3 The relative yields of m-cresol (3) and p-cresol (4) products4 formed have been found to be highly dependent upon the nature of the media used, with aqueous conditions favoring path A and anhydrous conditions favoring path B.3 We wish to report that t h e course of rearrangement of 4a P,Scu-dimethyl-5,6,7,8tetrahydro-2(4aH)-naphthalenone ( lb)*s5 is relatively insensitive to the conditions employed, in marked contrast with the behavior of the unsubstituted analog la.3 Moreover, in certain media the 8,8a-seco derivatives 12, 13a, and 13b are formed in 15-24y0 yield. These latter products represent a novel course for the dienonephenol rearrangement.
U'oodward and Singh'" were the first to demonstrate t h a t the major course of the rearrangement in acetic anhydride containing an acid catalyst is conversion to a p-cresol structure. Thus rearrangement of l a gave the p-cresol4a in 59ycyield.6 Evidence t h a t the rearrangement proceeds through a spiro carbonium ion1 (path B) was provided by Bloom,* who found that rearrangement of the &-methyl derivative l b under the same conditions gave the p-cresol 4b in 40yc yield' This result precluded a possible alternative mechanism, la path C, which would result in formation of the isomer 7b. Dreiding, Pummer, and Tomasewski3 found that when the rearrangement is carried out in aqueous mineral acid, instead of acetic anhydride, the major course becomes simple 1,2-methyl migratjon (path A ) , accompanied by a smaller amount of rearrangement by path B. Thus treatment of la with concentrated hydrochloric acid or 50% sulfuric acid gave principally the m-cresol 3a, accompanied by traces of 4a3 (see Table I). Similarly, androsta-1,4-dien-3,17-dione (8),which
CHARTI EFFECTOF MEDIAON
TABLE I COURSEOF THE DIENOKE-PHENOL REARRANGEMENT --Yields, 70--THE
p Cresol Dienone
OH R
4a-Methyl-5,6,7,8-tetrahydro-2(4aH)-naphthalenone (la) 4ndrosta-l,4-dien-3,17dione (8)
Acetic anhyd HCI3
50% HzS0h3 Acetic anhyd
HCI3
I*
*
59 -10 Trace 92
m-Cresol (3a or 10)
62 52 48
-26 -10
HBr3
la,R=H b,R=CHB
(4a or 9)
Conditions
55
in acetic anhydride gave the normal p-cresol product 9 in 92yc yield,s gave in hydrochloric or hydrobromic acid chiefly the m-cresol 10, along with a smaller amount of 9.3 $C
0
R
OH
R
0 4 - 4 4
e
10
8 (1) (a) R B. Woodward and T. Singh, J . Am. Chem. SOC.,73, 194 (1950); ( b l R . B. Woodward in A . Todd, "Perspectives i n Organic Chemistry," I n terscience Publishers, Inc., New York, S. Y . , 19.56, p. 178. (2) S R.1. Bloom, J . Am. Chem. S o r . , 80, 0280 (1958). 13) A . S. Dreiding, W. J. Pummer, and A . J . Tomasewski, ibrd , 1 6 , 3158 (1953) (4) For convenience and simplicity in the Discussion section, the terms "m-cresol" and "0-cresol" are used t o designate t h e methyl-substituted tetrahydronaphthol structures 9 and 4 ? respectively, and their steroidal analogs 10 a n d 9. ( 5 ) S. M Bloom, J . Or#. Chem.. I C , 278 (l9,59).
Of the four B-ring substitution patterns I-IV, involving the two possible migration centers of the spiro intermediate of path B, only compounds of types I (e.g., l a ) and I1 (e.g., 8) have been studied in detail. (6) Rearrangements conducted in acid anhydrides give phenol esters, which are usually hydrolyzed t o the correspending phenols without prior isolation. For simplicity only the phenols are represented here. (7) From a n analysis of the intrared spectrum of the crude product, Bloom concliirlrd t h a t t h e iii-cresol 3b had also been formed in ,?-lo"/;. yield.3 This material w a s n o t isolated iir characterized, however (8) A S. 1)reiding and A . Voltman, J . Am. Cham. S O L ,1 6 , 537 (1BR.l).
NOVELRINGB CLEAVAGE
Oct. 20, 1963
3281
Both of these types were found to rearrange concurrently via paths A and B and to show marked solvent effects on the relative involvement of the two paths. Type I11 has been investigated in the form of l b , but only to the extent to show t h a t path B, rather than C, operates in acetic anhydride.2 A detailed study of l b was undertaken to determine whether similar solvent effects are encountered in the rearrangement of dienones of type 111.
I
I1
I11 IV The results of this study are summarized in Table 11. Under all of the conditions examined, both anhydrous and aqueous, the known +cresol 4b2 was the predominant product. Formed in smaller yield in each case was a second phenol which had infrared absorption a t 11.56 p , characteristic of two isolated aromatic hydrog e n s g From analogy with previous the structure 3b was assigned. Support for this assignment was provided by a comparison of the aromatic region of the n.m.r. spectrum (one two-proton multiplet a t 3.42 7 ) with t h a t of several model trimethylphenols (see Table I TI), I t was found that the 0- and p-protons of substituted phenols appear at higher frequencies than m-protons, presumably because of increased shielding of the oand p-protons as a result of higher electron densities a t those positions. M3th 3,4,5-trimethylpheno1, in which both of the protons are in o-positions, only a single multiplet a t 3.49 T was observed. lo Final proof for the TABLE I1 REARRAXCEMENT O F 4a8,8cu-DIMETHYL-5,6,7,8-TETRAHYDRO 2(4aH)-NAPHTHALENOXE( l b ) P a t h B/ -Yields, 70a---. 4h
3b
13
12
path A
(CH3CO)zO 13 51 1 5 ( X = OH) . 5.1 (CF3CO)zO 11' 46 17 ( X = OH) 7b 6.4 H CI' 32 46 16 (X = CI) .. 1.9 507c HiSOa 29 63 ... 2.2 a Yields given for a typical run. These results were substantially reproduced in two to four similar determinations. Yields are based on material isolated by column chromatography unless otherwise indicated. * Estimated from gas chromatographic analS-sis. e Yields adjusted for 4y0 recovery of starting material.
TABLE 111 S.M.R. DATAFOR MODELTRIMETHYLPHENOLS
---
Chemical shifts, d----Aromatic H -CHI
Phenol
2,3,5-Trimethyl 3 42,b 3 54' 7 . 7 7 , 7 88 2,4,6-Trimethyl 3.23' 7 79 3,4,5-Trirnethyl 3 . 4gh 7 7 7 , i 91 2,4,5-Trimethyl 3 12,c 3.44' 7 82 Determined in 10% deuteriochloroform solution ; further o i l h o or para. dilution caused no changes in chemical shifts.
meta. (9) L . J. Bellamy, "Infrared Spectra of Complex Molecules," J. Wiley a n d Sons, New York, N. Y.,1958. p. 79. (IO) Similarly, I-methylestradiol 17-acetate (i) gives a single two-proton multiplet a t 3.52 7 . 1 1 However, 2,178-dihydroxy-4-methyl-l,3,5(10)estratriene 17-acetate (ii) gives two one-proton multiplets a t 3.31 a n d 3.43 r.11 Presumably t h e 3.31-7 peak is due t o t h e C - 1 proton, which is shifted downfield b y deshielding from t h e steroid nucleus.
HO i
ii
(11) P J K r o p p a n d W. F E r m a n , J. Am Chem SOL, 86, 2456 (1963)
I
160
I
170
1
180
I
190
I
200
I
210
C.RS
Fig. 1.-Curve A : Aromatic region of the proton spectrum of 5 4 5-hydroxy-o-tolyl)-2-pentene( 1 2 ) . The broadening of the peaks at 172.2 and 182.9 c.p.s. is believed t o arise from long range coupling with adjacent alkyl groups. Curve R : Computed spectrum assuming T A = 2.908 (144.5c.P.s.), T B = 3.397 (203.8 c.P.s.), TC = 3.340 (200.4 c.P.s.), JAB= 7.7 c.P.s., JBC= 4.0 c.P.s., and JAC = 0.
assignment 3b was obtained by dehydrogenation studies and an independent synthesis (described below). l 2 Also obtained in acetic anhydride was a third phenol, which was shown to be 5-(5-hydroxy-o-tolyl)-2-pentanol (13a). I n hydrochloric acid the analogous chloride 13b was formed instead, and in trifluoroacetic anhydride a mixture of 13a and the corresponding olefin 12 was obtained. All three of the phenols (12, 13a, 13b) exhibited the same three-proton pattern in the aromatic region (Fig. 1). This pattern may be analyzed by considering the two peaks a t 175.2 and 182.9 C.P.S. t o be one half of an AB quartet.I3" The other proton of this AB pair is spin coupled further to a third proton Hc. This coupling is manifested in the splitting of the high-field member of the AB doublet, which results in peaks a t 206.8 and 210.8 C.P.S. The low-field member of the HB doublet overlaps with the Hc peak a t 200.4 C.P.S. From = 7.7, JBC = 4.0> and this analysis, which gives JAB JAC = 0 c.P.s., a computer was used to calculate the s p e ~ t r u m . ' ~I t is seen that there is reasonable agreement between the experimental and calculated spectra so that the assumed parameters are probably those characteristic of this compound, In view of the observations mentioned above, that the protons ortho and para to the hydroxyl group appear a t higher field than protons meta to the hydroxyl group in substituted phenols, this pattern is consistent only with the 3,4-disubstituted structure. The low-field proton HA (2.91 T ) is identified with the C-3 proton (meta to the OH). The spin coupling constant JAB (7.7 c.P.s.) is characteristic of coupling with an o-proton (C-6). The proton a t 3.40 (HB) arises from the C-6 proton. There are two coupling constants associated from coupling with this proton, the 7.7 C.P.S. value (JAB) with the C-5 proton and a 4.0 C.P.S. value (JBc) from coupling with the meta C-2 pro to^.'^^ The C-2 proton, therefore, has a chemical shift of 3.34 7 . Finally in support of this interpretation, the spectrum of 3,4-dimethylphenol was found to be virtually superimposable in the aromatic region with that of the phenols 12 and 13. (12) T h e m-cresol 3b is also obtained from lb in yields u p t o 43Yc by photochemical rearrangement in acidic media.]] (13) L. M. Jackman, "Applications of Nuclear Magnetic Resonance Spectroscopy in Organic Chemistry," Pergamon Press, Inc., N e w York, X . Y., 1959: (a) pp. 89-90; ( b ) p 85, ( c ) pp. 53-35 (14) T h e calculations were made on an I B M 7090 computer using a program developed b y A. A. Bothner-By ( F R E Q I S T 111).
3282
Vol. 85
PAULJ. KROPP CHARTI1
TABLE11' N.M.R.EVIDENCE FOR PART STRUCTURE -CHCHI
1
>@ ?+
X --Chemical -H
x-
Compd.
shifts,
13a OH 6 18" 13b CIC 5 92" 13c OCOCHB 5 04" Unresolved multiplet. Doublet. Spectrum on the 3,5-dinitrobenzoate derivative
OH 12
4b 13a, R = H , X = OH b , R = H , X = C1 C, R = COCH3, X = OCOCHa
3,4-Dialkyl-substituted phenols could arise from a carbonium ion 1 1 , formed by opening of the spiro intermediate, 5b, or from the ion 6b, involving path C. The latter possibility was ruled out by the presence of a one-proton peak a t 6.18 T in the n.m.r. spectrum of 13a, which indicates a secondiry hydroxyl group.13c The methyl group and the methinyl proton of 13a, the diacetate 13c, and the chloride 13b showed the expected chemical shifts13ofor the part-structure -CH(X)CH3 (see Table IV). Similarly, the spectrum of 12 indicated the presence of two vinylic protons (4.52 7) and a vinylic methyl group (8.38 7) in the side chain. The structural assignments 12 and 13a were confirmed by facile acid-catalyzed cyclization of the compounds to the p-cresol 4b. Synthesis of m-Cresol 3b.-The structural assignment 3b for the m-cresol product was confirmed by an independent synthesis starting with the succinoylation of m-methylanisole, as outlined in Chart 111. This
7
-
7
-CHa
8 82* 8 48b 8 80h determined
cinoylation of phenols, phenol ethers are reported to give only p-substituted products. Clemmensen reduction of 14,15bfollowed by cyclization and treatment with methyl Grignard reagent gave the known dihydronaphthyl ether 17a. l8 Similarly the acid 15 was converted to the known tetralone 1619 and then to the dihydronaphthyl ether 19a. Fusion of 19a with pyridine hydrochloride a t 185' gave in 88% yield the dihydronaphthol 19b. However, when similar treatment of 17a was attempted, a larger scale was employed and a higher temperature (240') was required. Instead of the expected dihydronaphthol 17b, a 1 : 1 mixture of m-cresol 3b and the naphthol 18IS was obtained in 65y0yield, which presumably arose from disproportionation of 17b. The m-cresol 3b obtained by this route was found to be identical with the material formed by the acid-catalyzed rearrangement of the dienone l b . The naphthol 18 could also be obtained from 3b by dehydrogenation over palladium-charcoal in refluxing p-cymene. Discussion Although ring-B seco derivatives have been obtained previously under reductive, 'O enzymatic, or pyrolyticZ2 conditions for dienone-phenol conversions,
CHARTI11
OCH, 0
COzH
I
-
17a, R CH3 b,R=H
J
COzH
15
14
J
OCH,
16 CH,MgBr
I
OR
I
18
t
reaction is reportedI5 to give only P-(4-methoxy-2methyl-1-benzoyl)-propionic acid (14) in nitrobenzene. However, in the present work, in which a nitrobenzenetetrachloroethane solvent mixtureI6 was used, an approximately 1 : 1 mixture of 14 and the 2-methoxy-4methyl isomer 1517 was obtained. The occurrence of a significant amount of attack a t C-6 of rn-methylanisole is not unexpected, since i t is both ortho to the methoxyl group and para to the methyl substituent, but is not as hindered as C-2. Although mixtures of products arising from both ortho and para attack is common for the suc(15) (a) K . W. Rosenmund and D . Shapiro, Arch. P h a r m . , 274, 313 (1934) [Chem. A b s l r . , I S , 4048 11934)l; (b) K . D . Desai and M . A. Wali, Proc. I n d i a n A L Q Sei., ~ 6 8 , 144 (1937) [Chcm. A b s l r . , S I , 509 (1938)l; (c) D . Papa, E Schwenk, and H . Hankin, J . A m . Chcm. Soc., 69, 3018 (1947). 118) Cf.E Berliner, Org. Rencfcons, 6, 229 (1949). (17) J. J. Trivedi and K . S. Nargund, J . Univ,. Bombay, 10, Pt. 3 , 9 9 (1941) [Chem. A b s t v . , 36, 3801 (1942)l.
Pd-C p-cymene
3b
i
lSa,R-CHa b,R-H
to our knowledge the formation of 13a, 13b, and 12 represents the first reported example of ring B cleavage under the normal conditions of acid-catalyzed rearrangement. I t is also the first example of ring-B cleavage under any conditions involving prior rearrangement of ring B. The seco products 13 apparently arise from trapping of the cation 1 1 by the acid anhydride or by chloride ion. In the less nucleophilic trifluoroacetic anhydride, elimination to the olefin 12 can compete effectively with ester formation. 28 Although the alco(18) L. Ruzicka and L. Sternbach, H c l u . Chrm. A d a , I S , 355 (1940). (19) R . G. Cooke and H Dowd, Auslralian J . S c t . R e s . , SA, 780 (1952) [Chcm. A b s l r . , 43, 2022 (195411. (20) K Tsuda, E. Ohki, S. Nozoe, and K . Ikekawa, J . Org. Chem., $6, 2614 (1961). (21) R . M. Dodson and R . D . Muir, J . A m . C h e m . SOL.,33, 4827 (1961) (22) B . J , Magerlein and J. A . Hogg, Tefrahedvon. I , 80 (1958). (23) Since sulfuric acid has a very limited solubility in trifluoroacetic
NOVELRING B CLEAVAGE
Oct. 20, 1963
hol 13a or the olefin 12 may be formed in 50yosulfuric acid as well, they would undergo rapid cyclization to the p-cresol4b under these conditions and would not be found in the final reaction mixture. Treatment of pure 13a or 12 with 50% sulfuric acid gave 4b in quantitative yields. It is interesting to note that Friedrich and Winstein2* were able to detect no open-chain products (4-phenyl-lbutanol or 4-phenyl-1-butene) in the acetolysis or formolysis of the p-nitrobenzoates 20 and 21. Apparently ring expansion is considerably faster than ring opening in this system. However, in this case ring opening could give only a primary carbonium ion vs. a secondary ion in the case of 11. I n a formal sense the ring opening process is a reversal of the well-known formation of dienones bv the solvolysis of substituted 4-arylbutanol esters.25 0
I1
OCCeH4NOzI
21
The striking effect of media on the predominant course of rearrangement of the dienone l a is exhibited to a much lesser degree by the 8a-methyl derivative l b . Although the ratio path B/path A for l b does decrease approximately threefold in going from trifluoroacetic anhydride to aqueous conditions (see Table 11), it does not become less than one, and l b rearranges predominantly by path B under all of the conditions studied. This marked difference in sensitivity to media exhibited by l a and l b allows some additional insight into the delicate balance between paths A and B of the dienonephenol rearrangement and into the nature of media effects upon this balance.26 At first glance the occurrence of methyl migration (path A) in dienone-phenol rearrangements of compounds of the type 1 seems surprising. Although little information is available concerning the relative aptitudes of alkyl groups for migration from carbon to an electron-deficient carbon, Stiles and Mayer2' obtained the order t-butyl > ethyl > methyl from a study of the pinacol rearrangement in 50% sulfuric acid.28 The anhydride, rearrangements under these conditions might occur heterogeneously, t h u s accounting f o r t h e appearance of la. However, gas chromatographic studies suggest t h a t 12 is also formed i n small yield (about 1 %) in acetic anhydride. (24) E . C . Friedrich a n d S.Winstein, Telrnhedron Lellers, 475 (1962). (25) S. Winstein a n d R. Baird, J . A m . Chem Soc , 79, 756 (1957); S. Masamune, ibid., 83, 1009 (1961); L. Mandell, D Caine, a n d G . E . Kilpatrick, ibid., 83, 4457 (1961). (26) Although different temperatures are normally employed for t h e aqueous ( looo) and anhydrous (room temperature) conditions, t h e observed differences in product ratios cannot he a t t r i b u t e d t o a temperature effect. I n t h e present s t u d y substantially t h e same results were obtained in acetic anhydride a t 25 a n d looo. Dreiding, P u m m e r , a n d Tomasewski' report similar results from t h e t r e a t m e n t of 8 with hydrochloric acid a t room temperature or under reflux (27) M . Stiles a n d R. P. M a y e r , J . A m . Chem. Soc.. 81, 1497 (1959); see also P . Warrick, J r , a n d W H . Saunders, Jr., zbid , 84, 4095 (1962). (28) However, H . 0. House, E . J. Grubbs, a n d W. F. G a n n o n , rbzd., 82, 4099 (1960), obtained t h e order methyl propyl > ioopropyl 1-butyl from a study of t h e reaction of ketones with diazomethane; apparently t h e same order does not obtain in all t y p e s of molecular rearrangements. This m a y he due in p a r t t o t h e use of different media.
-
-
3283
best example for the present work comes from the dienone-phenol rearrangement itself, in which there is exclusive migration by the more highly substituted carbon of spiro intermediates of the type 5 . This is true even under aqueous conditions, in which methyl migration occurs to the greatest extent. I n aqueous media l a rearranges predominantly by path A, but 1b by path B. Of the various factors that might be ascribed to the influence of the additional equatorial methyl substituent of l b , i t does not seem likely that it is a steric effect-either one of increased steric interaction in one of the intermediates or one of steric interference with solvation of any of the intermediates. Indeed, if any added steric interaction exists in the case of Ib, it would appear to involve path B-which, in fact, is favored by the presence of the methyl s u b ~ t i t u e n t . ~Obviously ~ the course of rearrangement is not determined solely by the rates k l and k3, but also reflects kq since the presence of the methyl substituent of l b has such a pronounced effect. Apparently in aqueous media methyl migration can compete fairly well with two consecutive migrations involving methylene, but not with migration by methylene followed by methine migration. 30 In nonaqueous media path A cannot compete as effectively with path B in the case of either l a or lb. The increased aptitude for methyl migration under aqueous conditions could indicate preferential stabilization of that transition state by solvation. Further studies of the effects of structure and media on the course of the dienone-phenol rearrangement designed to elucidate the mechanistic features are in progress. Experimental Rearrangement of 4ap,8a-Dimethyl-5,6,7,8-tetrahydro-Z(4aH)naphthalenone (lb). A. In Acetic Anhydride.-Following the procedure of Bloom,2 462 mg. of the dienone Ib was treated with a total of 23 ml. of acetic anhydride containing 5 drops of sulfuric acid a t room temperature for 6 hr. Isolation as described2 gave 530 mg. of a colorless oily mixture of phenol acetates, which was found by gas chromatography and infrared analysis to contain no residual dienone. Hydrolysis p i t h ethanolic hydrochloric acid2 gave 415 nig. of a pale yellow oil, which was chromatographed on 15 g. of silica gel (Davison Chemical Co., 200 mesh). Elution with 900 ml. of 1 3 benzene-hexane gave 235 mg. (51Cj, yield)oof 4,8-dimethyl-5,6,7,8-tetrahydro-l-naphthol (4b), m . p . 90-91 . Recrystallization from petroleum ether gave colorless plates, m.p: 95-96', and ,,,A 12.42 p ; reported2 &.p. 93-84.5", 40% vield. Further elution with 600 ml. of 1 : 1 benzene-hexane gave 60 mg. (13:& yield) of 4,8-dimethyl-5,6,7,8-tetrahydro-Z-naphthol (Jb), m.p. 92-94'. Recrystallization of comparable material (29) I t should be noted t h a t in the case of an axial b p m e t h y l substituent considerable steric interaction witn t h e 4a-angular methyl group occurs in t h e formation of a spiro carbonium ion of t h e t y p e 6. This, along with increased eclipsing ot t h e o t h e r ring B substituents in spiro carbonium ion formation, is reflected in t h e exclusive rearrangement ot t h e dienone iii ?'in p a t h A ; c/. B. R . Davis a n d T . G . Halsall, J Chem. S o c . , 1833 ( 1 9 0 2 ) .
iii (30) In t h e case of steroids, in which methyl migration ( p a t h A) predominates over methinyl migration ( p a t h B or C ) in aqueous media, i t is not possible t o evaluate the effects of t h e bulky C a n d D rings on t h e course of t h e rearrangement F u r t h e r m o r e , t h e available d a t a do n o t indicate whether p a t h B or path C operates in this case. (31) Ultraviolet spectra were determined in absolute ethanol uring a Cary Model 1 4 spectrophotometer, and infrared spectra were obtained in 07, methylene chloride solution on a Perkin-Elmer Infracord spectrophotometer Gas chromatographic separations were effected a t 200' using a 5 i t X 0 . 2 5 in. column containing 20% GE-silicone fluid 96 on 60/80 mesh firebrick. Melting points were determined o n a micro-hotstage and are calibrated a n d corrected. N . m . r . spectra were obtained in deuteriochloroform solution with a Varian model A-GO spectrometer, using tetramethylsilane a s an internal s t a n d a r d . Microanalyses were performed b y Spang Microanalytical Laboratories, Ann Arbor, Mich.
3284
PAULJ. KROPP
Vol. 85
with 1 I. of 1 . 3 bezene-hexane, 232 mg. (46:h yield) of 4,8dimethyl-5,6,7,8-tetrahydro-l-naphthol ( 4 b ) , m.p. 95-96". Further elution gave 90 mg. of a colorless oil which was separated by gas chromatography into 55 mg. (11'4 yield) of crystalline 4,8-dimethyl-5,6,7,8-tetrahydro-2-naphthol (3b), m.p. 93Anal. Calcd. for C12HLs0: C, 81.77; H , 9.15. Found: 95", and 35 mg. (7%;yield) of 5-(5-hydroxy-o-tolyl)-2-pentene (12) C, 81.7; H , 9.1. as a colorless oil, A,, 2.75 and 6.20 p ; n.m.r. spectrum: 4.52 Elution with benzene and 1 : 9 ether-benzene gave 7 mg. of oily (2, m , CH-2 and -3), 7.80 ( m , 3, aromatic CHa), and 8.38 7 material which was discarded. Finally, elution with 600 ml. of ( m , 3, CH3-1). 1 : 3 ether-benzene gave 76 mg. (15y0yield) of 5-(5-hydroxy-oFinally, elution with 450 ml. of 1 : 3 ether-benzene gave 91 mg. tolyl)-2-pentanol ( 13a), m.p. 77-79'. Recrystallization twice (17% yield) of 5-( 5-hydroxy-o-tolyl)-2-pentanol(13a) as colorless from ether-hexane gave colorless needle clusters, m.p. 78-79'; needles, m.p. 77-79". , , ,A 2.74, 6.20, and 12.24 p , and A, 219 ( e 4600) and 280 nip Cyclization of 5-(5-Hydroxy-o-tolyl)-2-pentanol( 13a).--A solu( e 1500); n.m.r. spectrum: 6.18 ( m , 1, CH-2), 7.83 (s, 3, arotion of 26 mg. of alcohol 13a in 10 ml. of ethylene dichloride conmatic CH3), and 8.82 7 ( d , 3, J A B = 6, CH3-1). taining 0.2 ml. of boron trifluoride etherate was heated under reflux in an atmosphere of nitrogen. The reaction mixture was A n d . Calcd. for C12H1802: C, 74.19; H, 9.34. Found: diluted with 30 ml. of methylene chloride, washed with 30 nil. of C. 74.2; H , 9.4. water, dried over saturated sodium chloride solution and a n h y Treatment with a 2 : 1 mixture of pyridine-acetic anhydride drous sodium sulfate, and evaporated to dryness t o give 24 mg. of overnight a t room temperature gave an oily diacetate ( I ~ c ) , prisms, m.p. 91-07O. Recrystallization from hexane gave 18 tng. A,,. 5.68 and 5.78 p ; n.m.r. spectrum: 5.04 ( m , I, CH-2), of colorless plates, m . p . 96-97". The melting point was UII7.74 (s, 6, OCOCH3), 8.00 (s, 3, aromatic CHa), and 8.80 7 changed on admixture with an authentic sample of 4,8-dimethyl( d , 3, JAB = 6, CHP-1). 5,6,7,%tetra hydro- 1-naphthol (4b ) . Trea trnen t of a 5-mg . B. In 5OtJ Sulfuric Acid.-Following the general procedure of portion of 13a with 2 ml. of 5O'C sulfuric acid as described below Dreiding, Putnmer, and T o m a ~ e w s k i 1.00 , ~ g . of the dienone I b for 12 gave 4 nig. of a colorless oil which crystallized on seeding was treated with 10 ml. of 50% sulfuric acid a t 100" for 30 min. with 4b and which gave only one peak upon gas chromatographic under an atmosphere of nitrogen. The reaction mixture, which analysis. became turbid after about 15 min., was cooled to room temperaCyclization of S-(S-Hydroxy-o-tolyl)-Z-pentene( 12).--A [nix-' ture and extracted with a total of 250 ml. of ether. T h e comture of 23 mg. of olefin 12 in 2 mi. of 50'1; sulfuric acid was mainbined ether extracts were washed with water, saturated sodium tained a t 105" under an atmosphere of nitrogen for 30 min. bicarbonate solution, and saturated sodium chloride solution. The reaction misture was cooled, neutralized with excess satuThe combined aqueous portions were neutralized with sodium rated sodium carbonate solution, and extracted with two 5O-mI. bicarbonate and extracted with ether. The ether fractions were portions of ether. The combined ether extracts were dried over then dried over anhydrous sodium sulfate. Removal of solvent saturated sodium chloride solution and anhydrous sodium sulfate on a rotary evaporator a t 40' and aspirator pressure gave 1.01 g. and evaporated to dryness t o give 21 mg. of an amber oil which of a colorless oily mixture of phenols. Chromatographic separacrystallized on seeding with a specimen of 4,8-dimethyl-5,6,7,8tion on 30 g. of silica gel as described above gave 630 mg. (63C;. tetrahydro-I-naphthol (4b) to give colorless plates, ni . p . 93-96'; yield) of 4,8-dimethyl-5,6,7,8-tetrahydro-l-naphthol ( 4 b ) , m.p. mixture melting point with authentic 4b 93-97", 95-96", which showed no melting point depression on admixture Succinoylation of nz-Methylanisole,-.% modification of the with the material described in part h. general procedure of BerlinerL6was employed. Treatment of 49 Further elution gave 289 mg. (29y0 yield) of 4,8-dimethylg. (0.40 mole) of m-methylanisole with 42 g. (0.42 mole) of 5,6,7,8-tetrahydro-2-naphthol( 3 b ) , m.p., 92-94', Recrystallisuccinic anhydride and 112 g. (0.84 mole) of aluminum chlorid: zation from hexane provided colorless prism clusters, m . p . 94in 400 ml. of nitrobenzene and 100 ml. of tetrachloroethane a t 0 95', m.p. 94-96" when mixed with the material described above. for 3 days gave, after acidification and steam distillation, 50 g. C. In Hydrochloric Acid.-Following the procedure of Dreid(SSC/, yield) of colorless mixed crystals, m . p . 132-134.5". ing, Pummer, and T o m a s e ~ s k i 1.00 , ~ g. of the dienone l b \va; Separation by fractional recrystallization from acetone gave in treated with 10 ml. of concentrated hydrochloric acid a t 100 approximately equal amounts colorless needles, m .p. 138-139", for 45 min. under an atmosphere of nitrogen. The reaction and colorless prisms, m.p. 126-127'. Reported for P(4;niethmixture became turbid after 7 min. Isolation as described in oxy-2-methyl-l-benzoyl)-propionicacid ( 14)15 m.p. 138 , and part B gave 1.03 g. of a pale yellow oil, which was chromatofor ~-(2-methoxy-4-methyI-l-benzoyl)-propionic acid (IS)," m.p. graphed on 30 g. of silica gel. Elution with 1.5 1. of 1 : 3 benzene126". hexane gave 141 mg. of 4,8-dimethyl-5,6,7,8-tetrahydro-l3,5-Dimethyl-7,8-dihydro-l-naphthol(I9b).-Following the naphthol (4b), m.p. 96-97' and m.m.p. (with material described general procedure of Ruzicka and Sternbach,'* a solution of 5.73 in part A ) 96-97". g. (30 mmoles) of 3,4-dihydro-5-methoxy-7-niethyl-1(2H)Further elution with 2.4 1. of 1 . 3 benzene-hexane gave 306 mg. naphthalenone ( 16)19 in 25 ml. of anhydrous ether was added of 4,8-dimethyl-5,6,7,8-tetrahydro-2-naphthol ( J b ) , m.p. 93dropwise with stirring and ice-bath cooling under an atmosphere 94.5' and m.m.p. 93-95'. of nitrogeii to 25 ml. of a solution containing 80 mmoles of Elution with 2.7 1. of 1 : 1 benzene-hexane provided 180 mg. of methylrnagnesium bromide. The resulting mixture was heated Z-chloro-S-(S-hydroxy-o-tolyl)-pentane(13b) as a colorless oil, under reflux for 30 min., cooled t o room temperature, and then which was characterized as the J,S-dinitrobenzoate, fine colorless added to 50 ml. of iced lO'!i sulfuric acid. The aqueous misture needles, m.p. 93-94"; A,, 5.70, 6.12, 12.38 p ; n.m.r. spectrum: was extracted with three 50-1111. portions of ether, a n d the com5.92 ( m , 1, CH-2), 7.67 (s, 3, aromatic CHs), and 8.48 T ( d , bined ether extracts were washed with 50-ml. portions of water, 3, JAR= 6.5, CH3-1). saturated sodium carbonate solution, and saturated sodium chloride solution. Drying over anhydrous sodium sulfate and Anal. Calcd. for CISHIYO~ii2C1: C, 56.09; H, 4.71; S , removal of the solvent under reduced pressure gave a brown oil. 6.89; Cl, 8.72. Found: C, 55.9; H, 4.8; S , 6.8; CI, 9 . 1 . Distillation through a 6-in. Vigreux column gave 4.04 g. of 4,6Finally, elution with 1 : 19 ether-benzene gave 39 mg. of crystaldimethyI-8-methoxy-l,2-dih'ydronaphthalene (19a) as :I ci~lorless line starting dienone. The yields, adjusted for recovered startliquid, b.p. 110-113° a t 1.8 m m . , A,,,,, 6.20 and 12.00 p ; 1i.in.r. ing material, were 16, 32, and ISFA, respectively. spectrurri: 3.12 ( s , 1, CH-5), 3.54 (s, 1, CH-T), 4.26 ( m , 1, D. In Trifluoroacetic Anhydride.-A solution of 500 mg. of CH-3), 6.28 i s , 3, CHaO-), 7.73 ( s , 3 , CHa-6), and 8.02 7 ( m , 3, the dienone I b in 11 ml. of trifluoroacetic anhydride was stirred CHI-4). x i t h 5 drops of concentrated sulfuric acid a t room temperature A mixture of 350 mg. of the ether 19a and 3.6 g. of freslily in the dark for 5 hr. The reaction mixture was then poured into prepared anhydrous pyridine hydrochloride was maiiitaitied a t excess saturated sodium carbonate solution. After all of the 185' under an atmosphere of nitrogen for 1.5 hr. The reaction anhydride was hydrolyzed, the mixture was extracted with four mixture was cooled to room temperature, diluted with 100 1111. of 50-ml. portions of ether. The combined extracts were dried over water, and extracted with three 50-ml. portions of ether. The saturated sodium chloride solution and anhydrous sodium sulfate. combined ether extracts were washed with water, 10 Evaporation of the solvent a t reduced pressure gave 564 mg. of an chloric acid, water, and saturated sodium chloride, amber oil, which was dissolved in 25 ml. of mcthanol and treated dried over anhydrous sodium sulfate. Evaporation o with 2.5 nil. of IO", potassium carbonate solution for 2 hr. a t vent gave 349 mg. of a partially crystallirie amber oil, which was room temperature. Removal of the methanol a t reduced preschroinatographed on 15 g. of silica gel. Elution with 1.2 I . of sure, extraction of the aqueous residue with three 100-ml. por1 . 3 benzene-hexane gave 285 mg. (887; yield) of colr)rless tions of ether, drying of the combined extracts over saturated needles, ri1.p. 114-117". Recrystallization from hexane gave sodium chloride solution and anhydrous sodium sulfate, and 2.75, 6.20, 6.34, and 11.92 edles, 1n.p. 117-118.,5"; A, evaporation of the solvent a t reduced pressure gave 507 mg. of an 221 (E 24,800) and 267 mp ( e 10,600); n.m.r spectrum: amber oil. Chromatography on 15 g. of silica gel gave, on elution 3.30 ( s , 1, CH-4), 3.50 (s, 1, CH-2), 4.11 ( r n , 1, CH-K), 7.72 ( s , 3 , CHa-3), and 7.98 T ( m , 3, CH3-5). ( 3 2 ) (a) Indicates multiplicity I s = singlet, d = doublet. t = triplet, A n d . Calcd. for Cl?HlrO: C , 82.72; H , 8.111. Found: C, q = q u a r t e t , a n d m = multiplet), integration, a n d assignment: (b) coupling 83.0; H , 8.3. constants given in c p . s . from hexane gave colorless prism clusters, m.p. 95.5-96.0'; 283 mp ( e 1,900); n.m.r. spectrum: 3.42 ( m , 2, CH-1 and -3),32n7.82 (s, 3, CH3-4), and 8.76 7 ( d , 3, JAB = 7, CH3-8).3*b Amax 2.75, 6.20, and 11.56 p , and A,
PHOTOCHEMICAL DEGRADATION OF RIBOFLAVIN
Oct. 20, 1963
3285
Cleavage of 4,8-Dimethyl-6-methoxy-l,2-dihydronaphthalene obtained from the acetic anhydride-sulfuric acid rearrangement of the dienone I b , as described in part A above, was heated under (17a).-A mixture of 1.68 g. of the ether 17al8 and 18 g. of freshly reflux with 50 ml. of p-cymene and 200 mg. of 10% palladiumprepared anhydrous pyridine hydrochloride was maintained a t on-charcoal in a nitrogen atmosphere for 76 hr. The solvent 240’ under an atmosphere of nitrogen for 2 hr. Isolation a s was removed by steam distillation and the resulting aqueous described above gave 1.35 g. of an amber oil, which was chromaresidue in the distilling flask (approximately 250 ml.) was passed tographed on 50 g. of silica gel. Elution with 2.5 1. of 1 : l through a paper filter while still hot. On cooling, the aqueous benzene-hexane gave 0.99 g. (65% yield) of colorless needles solution yielded 86 mg. of 4,8-di?ethyl-Z-naphthol ( 18)leas colorwhich was shown by gas chromatographic analysis to be a 1: 1 less fluffy needles, m . p . 153-154 . Recrystallization from benmixture of 4,8-dimethyl-5,6,7,8-tetrahydro-2-naphthol( 3 b ) and zene-hexane failed t o change the melting point. Admixture 4,8-dimethyl-2-naphthol ( 18).18 Recrystallization from etherwith a portion of the material obtained from the dihydronaphthyl hexane gave 304 mg. of naphthol 18 as colorless needles, m.p. ether 17a as described above gave a melting point of 152-153’; 152-164”. The phenol 3b was separated from a portion of the reportedle for 18: m.p. 151.5-152.5. mother liquors by gas chromatography t o give colorless compact needle clusters, m . p . 94-95” after final recrystallization from Anal. Calcd. for C12H120: C, 83.69; H , 7.02. Found: C , hexane. The melting point was unchanged on admixture with 83.3; H, 7.1. the material obtained from rearrangement of the dienone I b Acknowledgments.-The author is particularly inin acetic anhydride as described above. Dehydrogenation of 4,8-Dirnethyl-5,6,7,8-tetrahydro-Z-naph- debted to Dr. T. J. Flautt for help with the interpretatho1 (3b).-Following the general procedure of Wenkert and tion and calculation of n.m.r. spectra and to Drs. Dave,33 500 mg. of 4,8-dimethyl-5,6,7,8-tetrahydro-2-naphthol W. F. Erman and C. D. Broaddus for helpful discus(33) E. Wenkert and K . G . D a v e , J . A m . Cham. Soc., 84, 94 (1962)
[CONTRIBUTION FROM
THE
sions during the course of the work.
DEPARTMENT O F BIOCHEMISTRY A N D BIOPHYSICS, IOWA STATE UNIVERSITY, AMES,IOWA]
The Photochemical Degradation of Riboflavin’r2 BY EDDIE
c. S M I T H 3 AND DAVIDE .
METZLER
RECEIVEDMAY3, 1963 Anaerobic photobleaching of riboflavin followed by reoxidation with air is shown by means of microbiological assays and thin layer chromatography t o produce a mixture of flavins including unchanged riboflavin, lumiflavin, lumichrome, and two additional compounds. T h e major new product has been identified as 6,7-dimethyl9-formylmethylisoalloxazine by means of its chromatographic behavior and chemical reactions. Merck AG, Darmstadt, Germany. Freshly boiled glass-reohm-’ distilled water with a specific conductance of 2.2 X was used. Apparatus.-All spectral measurements were made on a Beckman DU spectrophotometer which had a special cell compartment cover t o accommodate the cells used for anaerobic measurements. These cells consisted of two pieces connected by a 14/20 standard tapered joint. The base piece was made b y sealing a 7-cm. length of Pyrex tubing t o a standard 1-cm. Pyrex cuvette and the t o p section was made by sealing a 3-cm. piece of 12-mm. Pyrex tubing containing a medium sintered-glass filter t o a stopcock. T h e function of the sintered-glass filter was t o prevent loss of solution through “bumping” during evacuation. The Desaga thin layer chromatography apparatus was used in the preparation of chromatography plates. Thin Layer Chromatography.-Silica gel G plates (20 cm. by 20 c m . ) of 250 p thickness were used. Kormally about 10-3 micromole of flavin (10 p l . of lo-‘ M solution) was applied a t spots 1 cm. apart on the plate. Two solvent systems were used: butanol (7):ethanol ( 2 ) :water ( 1 ) and water saturated with isoamyl a l c o h ~ l . The ~ spots were detected after chromatography Experimental by their blue or yellow-green fluorescence under a n ultraviolet Materials.-Riboflavin (6,7-dimethyl-9-(~-l’-ribityl)-isoalloxa- light. zine), a gift from Merck & Co., was recrystallized twice from 2 N Microbiological Assay.-The procedure of Snell and Strong“ acetic acid and was then extracted with chloroform t o remove the based on the titration of acid produced during the growth of lumichrome impurity. Lumiflavin was synthesized by the Lactobacillus casei was employed. method of Hemmerich, et al.” Lumichrome was prepared by the Anaerobic Photolysis.-A M solution of riboflavin was photolysis of riboflavin in 50% methanol-HZ0 solution by sunplaced in a modified Thunberg tube and evacuated, first with a light.’z T h e method of Fall and Petering13 was used t o prepare water aspirator for 15 min. and then with a mechanical pump for 6,7-dimethyl-9-formy1methylisoalloxazine and 6,7-dimethyl-9the same length of time. During the evacuation the tubes were (2’-hydroxyethyl)-isoalloxazine from riboflavin. Riboflavin shaken vigorously several times. The solution was illuminated assay medium was obtained from Difco Laboratories. Silica gel with a 15-watt Sylvania daylight type fluorescent lamp placed G and silica gel (less than 0.08 mm.) were obtained from E. approximately 23 c m . from the sample for 16-24 hr. The photoreduction and subsequent oxidation, when oxygen was admitted, (1) Supported by grant N o . G-12339 from the National Science Foundawere followed spectrophotometrically a t 445 mlr. For larger tion. samples u p t o 2 1. in volume, a special apparatus was constructed (2) A preliminary report appeared in Federation Proc., 22, 591 (1963). which consisted of two 3-1. round-bottom flasks connected with (3) Procter and Gamble Fellow, September, 1961-May, 1962. 300 cm. of 1-cm. Pyrex tubing, coiled in such a way t h a t the light ( 4 ) R . Kuhn, H. Rudy, and Th. Wagner-Jauregg, B o . , 66, 1950 (1933). source could be placed directly above i t . After a lo-‘ 121ribo(5) B. Holmstrom and G. Oster, J . A m . Chem. Soc., 83, 1867 (1961). flavin solution was placed in flask A, the whole apparatus was 16) G . Oster, J . S.Bellin, and B . Holmstrljm, Exparrcntia, 18, 249 (1962). evacuated, by means of a mechanical vacuum pump, for 45 min. (7) J . R . Merkel and W . J . Sickerson, Biochim. Biophrs. Acta, 14, 303 The solution then was forced through the coils into flask B by 1 (1954). a t m . of nitrogen (purified by passing over hot copper and stored (8) L. P . Vernon, i b i d . , 36, 177 (1959). n a 12-1. reservoir). The desired amount of photobleaching could ( 9 ) W . J . Nickerson and G . Strauss, J . A m . Chcm. SOL.,811, 5007 (1960). be accomplished in 2 ways. First, the flow rate of the solution (10) G . Strauss and W . J . Nickerson, ibid., 83, 3187 (1961). through the coils could be controlled b y introducing several (11) P . Hemmerich, S.Fallab, and H . Erlenmeyer, Hela. C h i m . Acto, 39, sintered glass filters at the end of the coils and, secondly, by 1242 (1956)
Introduction When riboflavin is illuminated anaerobically the yellow color fades and the isoalloxazine ring becomes red ~ c e d . ~ .Since 5 riboflavin is known to induce the photooxidation of a variety of compounds, i t is reasonable to assume with the early workers in the field that the anaerobic fading of riboflavin results from photooxidation of its own ribityl side chain. Although a considerable body of evidence, recently reviewed by Oster, et a1.,6 supports this idea, some workers have proposed that the hydrogen for the reduction of the isoalloxazine With these ring comes from the cleavage of two contradictory views in mind, we have performed several experiments which help to clarify the nature of the anaerobic photolysis of riboflavin.
(12) P . Karrer, H. Salomon, K . Schopp, F . Scblitter, and H. Fritzsche,
ibid., 17, 1010 (1934). (13) H. H . Fall and H . G . Petering, J . A m . Chem. Soc., 78, 377 (1966).
(14) E . E. Snell and F . M. Strong, I n d . E n g . C h e m . , A n a l . E d , 11, 3.18 (1939).
